title: Reduced phosphate transport in the renal proximal tubule cells in cystinosis is due to decreased expression of transporters rather than an energy defect.
abstract: Nephropathic cystinosis is an autosomal recessive disorder caused by mutations in the CTNS gene [1], which encodes for a transporter (cystinosin) responsible for cystine efflux from lysosomes. In cystinotic renal proximal tubules (RPTs), the defect in cystinosin function results in reduced reabsorption of solutes by apical Na(+)/solute cotransport systems, including the Na(+)/phosphate (Pi) cotransport system [2]. However the underlying molecular mechanisms are unknown, given the lack of an appropriate cellular model. To obtain such a model system, we have knocked down cystinosin with siRNA in primary RPT cell cultures. An 80% reduction in cystinosin strongly inhibited Na(+) dependent Pi uptake (70%). Although this finding could be explained by a direct effect on transporters as well as by altered energetics (the ATP level dropped by 52%), our results demonstrate a lack of involvement of Na, K-ATPase, and a reduction in the number of NaPi2a transporters.
authors.affiliation: Department of Biochemistry, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA. biochtau@buffalo.edu
authors.forename: Mary L
authors.initials: ML
authors.lastname: Taub
authors.forename: James E
authors.initials: JE
authors.lastname: Springate
authors.forename: Facundo
authors.initials: F
authors.lastname: Cutuli
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003554:Cystinosis; D004734:Energy Metabolism; D005198:Fanconi Syndrome; D055785:Gene Knockdown Techniques; D017136:Ion Transport; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D009404:Nephrotic Syndrome / Q000235:genetics / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011817:Rabbits; D012964:Sodium / Q000378:metabolism; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000235:genetics / Q000378:metabolism*
chemical_list: D026921:Amino Acid Transport Systems, Neutral; D010710:Phosphates; D034741:RNA, Small Interfering; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D000255:Adenosine Triphosphate; D012964:Sodium